Francisella tularensis is a gram-negative bacterium and one of the top-priority agents ("Class A") most likely to pose a potential risk to national security. Although much has been learned from a mouse model using an attenuated strain of Francisella, Francisella tularensis live vaccine strain (LVS), little is known about how mice respond to virulent Francisella Type A strains (SCHU S4) with regard to immunity to inhalation exposure. There are few studies of virulent Type A strains of Francisella using mice and/or in mice exposed via inhalation challenge. The immune functions important for protection against intranasal or inhalation exposure to Francisella are still not completely understood or resolved. Studies in the mouse model of LVS have shown that cell-mediated immunity has an important function in host defense, but there is also new and recent evidence that antibodies play an important role in immunity. We recently developed a mouse model to assess development of protective immunity to intra-nasal challenge with virulent Francisella (SCHU S4). Mice challenged intra-nasally with a lethal dose of SCHU S4 and then treated with the drug levofloxacin were not only cured, but also developed protective immunity against intra-nasal re-challenge with SCHU S4. Importantly, we showed that serum from these immune mice protects na[unreadable]ve mice from an intra-nasal infection with a lethal dose of SCHU S4. Our overall goal is to test the hypothesis that antibody specific for bacterial proteins can be protective for mice following aerosol challenge with virulent Francisella tularensis (SCHU S4) and that the bacterial antigens recognized by protective antibodies can be used as an effective vaccine. The specific aims to test this hypothesis are as follows: 1) To optimize the protective immunity and antibody responses generated in mice following aerosol challenge with virulent Francisella and treated with levoflloxacin and 2) To identify and characterize the important antigens involved in protection which are identified by antisera generated in mice following aerosol challenge with Francisella and treated with levofloxacin. PUBLIC HEALTH RELEVANCE: Francisella tularensis is a bacterium that is one of the most infectious pathogens known and can be used as a bioweapon against the public via inhalation exposure. Unfortunately, little is currently known about how to protect the public against such a threat. This application will further our knowledge about this bacterium by developing an animal model for investigating future vaccine development